Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhes...

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Published in:Cancer cell Vol. 33; no. 5; p. 937
Main Authors: Churchman, Michelle L, Qian, Maoxiang, Te Kronnie, Geertruy, Zhang, Ranran, Yang, Wenjian, Zhang, Hui, Lana, Tobia, Tedrick, Paige, Baskin, Rebekah, Verbist, Katherine, Peters, Jennifer L, Devidas, Meenakshi, Larsen, Eric, Moore, Ian M, Gu, Zhaohui, Qu, Chunxu, Yoshihara, Hiroki, Porter, Shaina N, Pruett-Miller, Shondra M, Wu, Gang, Raetz, Elizabeth, Martin, Paul L, Bowman, W Paul, Winick, Naomi, Mardis, Elaine, Fulton, Robert, Stanulla, Martin, Evans, William E, Relling, Mary V, Pui, Ching-Hon, Hunger, Stephen P, Loh, Mignon L, Handgretinger, Rupert, Nichols, Kim E, Yang, Jun J, Mullighan, Charles G
Format: Journal Article
Language:English
Published: United States 14.05.2018
Subjects:
Animals
Child
Female
Frameshift Mutation
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Ikaros Transcription Factor - genetics
Ikaros Transcription Factor - metabolism
Male
Mice
Neoplasm Transplantation
Pedigree
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Sequence Analysis, DNA
drug response
ALL
germline genetic variation
acute lymphoblastic leukemia
IKAROS
predisposition
immunodeficiency
IKZF1
familial leukemia
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary:Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.
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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2018.03.021